The placebo effect has received increased attention in both the adult and youth Major Depressive Disorder (MDD) treatment literatures. Approximately 60% of the symptom improvement experienced by clinically depressed patients in studies of antidepressants or psychotherapy may be attributable to factors underlying the placebo effect (e.g., patients' expectations of symptom improvement). However, the mechanisms through which the placebo effect results in depressive symptom improvement remain poorly understood. Indeed, the National Institute of Health has called for increased research in this area (RFA-DA-12- 003, RFA-DA-12-004). A greater understanding of precisely how and why depressed patients improve in treatment could ultimately lead to the development of more effective and efficient treatments for this recurrent and highly debilitating disorder. An F32 postdoctoral fellowship would allow the applicant to investigate several promising neural and psychotherapeutic mediators of placebo response in psychotherapy for adolescent MDD. More specifically, given their role in reward mechanisms (including the expectation of reward), dopamine and the anterior cingulate cortex (ACC) may play important roles in mediating placebo response in MDD treatment. Indeed, the administration of a placebo may be conceptualized as eliciting the expectation of a particular type of reward (i.e., symptom improvement). Based on this framework, the current proposal focuses on the feedback-related negativity (FRN) and feedback-related positivity (FRP), two well-established electrophysiological indices of dopamine-mediated reinforcement learning processes, which are hypothesized to originate from dorsal ACC and striatal regions. Directly relevant to the proposed research, both FRN and FRP dysfunctions have emerged in MDD. Specifically, relative to controls, depressed adults have been characterized by larger FRN amplitude following negative feedback and blunted FRP amplitude in response to the expectation of a reward and reward outcome. Under the expert guidance of Dr. Diego Pizzagalli (primary mentor), a leader in the study of the neurobiological underpinnings of depression, the applicant will receive critical training in collecting, processing and analyzing high-density event-related potentials (ERP) data to assess these neural variables within the context of a clinical trial of MDD treatment. In addition, with regards to psychotherapeutic mechanisms that may underlie placebo response, the current study will investigate the mediating role of (1) the therapeutic alliance between therapists and patients, as well as (2) the extent to which patients acquire and utilize the central cognitive, behavioral and interpersonal skills encouraged in modern psychotherapy. Dr. John Weisz (secondary mentor) will provide key mentorship in the proper conduct of clinical trials of psychotherapy for MDD. Collectively, the proposed tailored research training plan will allow the applicant to acquire new skills and knowledge in neuroscientific approaches to depression, which will complement current expertise in psychotherapy research. PUBLIC HEALTH RELEVANCE: Despite the growing body of research supporting the efficacy of psychotherapy for the treatment of clinical depression in adolescents, very little is known regarding why and how psychotherapy works. The goal of the project is to investigate promising neurobiological and psychotherapeutic processes that may help explain why and how depressed adolescents improve in therapy. An understanding of the active ingredients and mechanisms of symptom improvement in depression treatment is critical, as it may ultimately lead to the development of more effective and efficient interventions for depression in youth.